In silico whole-genome scanning of cancer-associated nonsynonymous SNPs and molecular characterization of a dynein light chain tumour variant
In silico whole-genome scanning of cancer-associated nonsynonymous SNPs and molecular characterization of a dynein light chain tumour variant
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DOI：
10.1038/sj.onc.1208745
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发表时间：
2005-09-08
期刊：
影响因子：
8
通讯作者：
Zhang, MJ
中科院分区：
文献类型：
--
作者：
Aouacheria, A;Navratil, V;Zhang, MJ
近十年来，癌症遗传学积累了大量数据，为人类基因组中癌症基因的定位开辟了前所未有的途径。单核苷酸多态性（SNPs）是人类最常见的DNA变异形式，已成为癌症关联研究的宝贵工具。这些基因型标记可用于分析候选基因的等位基因与恶性表型的关系，并可能为恶性肿瘤的遗传方式提供新的线索。癌症发病的特征在这个面向癌症的研究中，我们详细介绍了一个SNP挖掘策略的基础上，公开可用的数据库之间的表达序列标签的分析。我们的全基因组方法提供了一个全面和公正的描述非同义SNP（nsSNP）在肿瘤与正常组织。为了进一步了解遗传变异和改变的表型之间的可能关系，将nsSNP的一个子集的位置映射到已知对蛋白质功能至关重要的蛋白质结构域上。还使用计算方法来预测这些癌症相关nsSNP对蛋白质结构和功能的潜在影响。我们通过详细的生物化学和结构表征的一个以前未知的癌症相关的突变（G79C）影响8 kDa的动力蛋白轻链（DNCL 1）来说明我们的方法。
Last decade has led to the accumulation of large amounts of data on cancer genetics, opening an unprecedented access to the mapping of cancer genes in the human genome. Single-nucleotide polymorphisms ( SNPs), the most common form of DNA variation in humans, emerge as an invaluable tool for cancer association studies. These genotypic markers can be used to assay how alleles of candidate genes correlate with the malignant phenotype, and may provide new clues into the genetic modi. cations that characterize cancer onset. In this cancer-oriented study, we detail an SNP mining strategy based on the analysis of expressed sequence tags among publicly available databases. Our whole-genome approach provides a comprehensive and unbiased description of nonsynonymous SNPs ( nsSNPs) in tumoral versus normal tissues. To gain further insights into the possible relationships between genetic variation and altered phenotype, locations of a subset of nsSNPs were mapped onto protein domains known to be critical for protein function. Computational methods were also used to predict the potential impact of these cancer-associated nsSNPs on protein structure and function. We illustrate our approach through the detailed biochemical and structural characterization of a previously unknown cancer-associated mutation ( G79C) affecting the 8 kDa dynein light chain ( DNCL1).